Process for preparing taxoids

ABSTRACT

The invention relates to a process for preparing taxoids of formula I herein that includes the steps of esterifying a baccatin III derivative of the formula VI herein, treating the compound obtained in acidic medium, and optionally removing a protecting group to give the desired taxoid product.

This is a division of application Ser. No. 08/162,984, filed Dec. 8,1993 pending.

The present invention relates to new taxoids of general formula:##STR1## their preparation and pharmaceutical compositions containingthem.

In general formula (I),

Ar represents an aryl radical,

R represents a hydrogen atom or an acetyl, alkoxyacetyl or alkylradical,

R₁ represents a benzoyl radical or a radical R₂ --O--CO-- in which R₂represents:

a straight or branched alkyl radical containing 1 to 8 carbon atoms, analkenyl radical containing 2 to 8 carbon atoms, an alkynyl radicalcontaining 3 to 8 carbon atoms, a cycloalkyl radical containing 3 to 6carbon atoms, a cycloalkenyl radical containing 4 to 6 carbon atoms or abicycloalkyl radical containing 7 to 11 carbon atoms, these radicalsbeing optionally substituted by one or more substituents chosen fromhalogen atoms and hydroxy radicals, alkyloxy radicals containing 1 to 4carbon atoms, dialkylamino radicals in which each alkyl portion contains1 to 4 carbon atoms, piperidino radicals, morpholino radicals,1-piperazinyl radicals (optionally substituted at position 4 by an alkylradical containing 1 to 4 carbon atoms or by a phenylalkyl radical whosealkyl portion contains 1 to 4 carbon atoms), cycloalkyl radicalscontaining 3 to 6 carbon atoms, cycloalkenyl radicals containing 4 to 6carbon atoms, phenyl radicals, cyano radicals, carboxy radicals oralkyloxycarbonyl radicals whose alkyl portion contains 1 to 4 carbonatoms,

or a phenyl radical optionally substituted by one or more atoms orradicals chosen from halogen atoms and alkyl radicals containing 1 to 4carbon atoms or alkyloxy radicals containing 1 to 4 carbon atoms,

or a saturated or unsaturated 4- to 6-membered nitrogen-containingheterocyclyl radical optionally substituted by one or more alkylradicals containing 1 to 4 carbon atoms,

it being understood that the cycloalkyl, cycloalkenyl or bicycloalkylradicals may be optionally substituted by one or more alkyl radicalscontaining 1 to 4 carbon atoms.

Preferably, Ar represents a phenyl or α- or β-naphthyl radicaloptionally substituted by one or more atoms or radicals chosen fromhalogen atoms (fluorine, chlorine, bromine, or iodine) and alkyl,alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio,hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino,alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxy,alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro andtrifluoromethyl radicals, it being understood that the alkyl radicalsand the alkyl portions of the other radicals contain 1 to 4 carbonatoms, that the alkenyl and alkynyl radicals contain 2 to 8 carbon atomsand that the aryl radicals are phenyl or α- or β-naphthyl radicals oralternatively Ar represents a 5-membered aromatic heterocyclic radicalcontaining one or more atoms, which are identical or different, chosenfrom nitrogen, oxygen or sulphur atoms, optionally substituted by one ormore substituents, which are identical or different, chosen from halogenatoms (fluorine, chlorine, bromine or iodine) and alkyl radicalscontaining 1 to 4 carbon atoms, aryl radicals containing 6 to 10 carbonatoms, alkoxy radicals containing 1 to 4 carbon atoms, aryloxy radicalscontaining 6 to 10 carbon atoms, amino radicals, alkylamino radicalscontaining 1 to 4 carbon atoms, dialkylamino radicals in which eachalkyl portion contains 1 to 4 carbon atoms, acylamino radicals in whichthe acyl portion contains 1 to 4 carbon atoms, alkoxycarbonylaminoradicals containing 1 to 4 carbon atoms, acyl radicals containing 1 to 4carbon atoms, arylcarbonyl radicals in which the aryl portion contains 6to 10 carbon atoms, cyano radicals, carboxy radicals, carbamoylradicals, alkylcarbamoyl radicals in which the alkyl portion contains 1to 4 carbon atoms, dialkylcarbamoyl radicals in which each alkyl portioncontains 1 to 4 carbon atoms or alkoxycarbonyl radicals in which thealkoxy portion contains 1 to 4 carbon atoms.

More particularly, Ar represents a phenyl, 2- or 3-thienyl or 2- or3-furyl radical optionally substituted by one or more atoms or radicals,which are identical or different, chosen from halogen atoms and alkyl,alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylaminoand trifluoromethyl radicals.

Still more particularly, Ar represents a phenyl radical optionallysubstituted by a chlorine or fluorine atom or by an alkyl (methyl),alkoxy (methoxy), dialkylamino (diethylamino), acylamino (acetylamino)or alkoxycarbonylamino (tert-butoxycarbonylamino) or 2- or 3-thienyl or2- or 3-furyl radical.

Of even more special interest are the products of general formula (I) inwhich Ar represents a phenyl radical and R₁ represents a benzoyl ortert-butoxycarbonyl radical.

According to the present invention, the new taxoids of general formula(I) can be obtained from a product of general formula: ##STR2## in whichAr and R₁ are defined as above and R₃ and R₄, which are identical ordifferent represent a hydrogen atom or an alkyl radical containing 1 to4 carbon atoms, or an aralkyl radical whose alkyl portion contains 1 to4 carbon atoms and the aryl portion preferably represents a phenylradical optionally substituted by one or more alkoxy radicals containing1 to 4 carbon atoms, or an aryl radical preferably representing a phenylradical optionally substituted by one or more alkoxy radicals containing1 to 4 carbon atoms, or alternatively R₃ represents an alkoxy radicalcontaining 1 to 4 carbon atoms or a trihalomethyl radical such astrichloromethyl or a phenyl radical substituted by a trihalomethylradical such as trichloromethyl and R₄ represents a hydrogen atom, oralternatively R₃ and R₄ form, together with the carbon atom to whichthey are attached, a 4- to 7-membered ring, and G₁ represents a hydrogenatom or an acetyl, alkoxyacetyl or alkyl radical or a hydroxy-protectinggroup, the procedure being carried out, according to the meanings of R₃and R₄, in the following manner:

1) when R₃ represents a hydrogen atom or an alkoxy radical containing 1to 4 carbon atoms or an optionally substituted aryl radical and R₄represents a hydrogen atom, the product of general formula (II) istreated in acidic medium in order to obtain a product of generalformula: ##STR3## in which Ar, R₁ and G₂ are defined as above, whose G₁radical is, if necessary, replaced by a hydrogen atom.

The deprotection of the side chain of the product of general formula(II) can also be carried out in the presence of an inorganic acid(hydrochloric acid or sulphuric acid) or an organic acid (acetic acid,methanesulphonic acid, trifluoromethanesulphonic acid orp-toluenesulphonic acid), used alone or in the form of a mixture, theprocedure being carried out in an organic solvent chosen from alcohols(methanol, ethanol or isopropanol), ethers (tetrahydrofuran, diisopropylether or methyl t-butyl ether), esters (ethyl acetate, isopropyl acetateor n-butyl acetate), aliphatic hydrocarbons (pentane, hexane orheptane), halogenated aliphatic hydrocarbons (dichloromethane or1,2-dichloroethane), aromatic hydrocarbons (benzene, toluene or xylenes)and nitriles (acetonitrile) at a temperature of between -10° and 60° C.,preferably between 15° and 30° C. The acid may be used in a catalytic orstoichiometric quantity or in excess.

The deprotection can also be carried out under oxidizing conditions,using for example ammonium cerium (IV) nitrate in an acetonitrile-watermixture or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in water.

The deprotection can also be carried out under reducing conditions, forexample by hydrogenolysis in the presence of a catalyst.

When G₁ represents a protecting group, it is preferably a2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy) carbonylradical whose replacement by a hydrogen atom is carried out using zinc,optionally combined with copper, in the presence of acetic acid, at atemperature of between 20° and 60° C. or by means of an inorganic ororganic acid such as hydrochloric acid or acetic acid in a solution inan aliphatic alcohol containing 1 to 3 carbon atoms or in an aliphaticester such as ethyl acetate, isopropyl acetate or n-butyl acetate in thepresence of zinc optionally combined with copper, or alternatively, whenG₁ represents an alkoxycarbonyl radical, its optional replacement by ahydrogen atom is carried out by treatment in alkaline medium or by theaction of a zinc halide under conditions which do not affect the rest ofthe molecule. Generally, the alkaline treatment is carried out by theaction of ammonia in aqueous-alcoholic medium, at a temperature close to20° C. Generally, the treatment with a zinc halide, preferably zinciodide is carried out in methanol at a temperature close to 20° C.

2) when R₃ and R₄, which are identical or different, represent an alkylradical containing 1 to 4 carbon atoms, or an aralkyl radical whosealkyl portion contains 1 to 4 carbon atoms and the aryl portion ispreferably an optionally substituted phenyl radical, or alternatively R₃represents a trihalomethyl radical or a phenyl radical substituted by atrihalomethyl radical and R₄ represents a hydrogen atom, oralternatively R₃ and R₄ form, together with the carbon atom to whichthey are attached, a 4- to 7-membered ring, the product of generalformula (II) is converted to the product of general formula: ##STR4## inwhich Ar and G₁ are defined as above, which is acylated by means ofbenzoyl chloride or a reactive derivative of general formula:

    R.sub.2 --O--CO--X                                         (V)

in which R₂ is defined as above and X represents a halogen atom(fluorine or chlorine) or a residue --O--R₂ or --O--CO--O--R₂, to give aproduct of general formula (III) in which Ar, R₁ and G₁ are defined asabove, whose G₁ radical is, if necessary, replaced by a hydrogen atom.

The products of general formula (IV) can be obtained by treating aproduct of general formula (II), in which Ar, R₁ and G₁ are defined asabove, R₃ and R₄, which are identical or different, represent an alkyl,aralkyl or aryl radical, or alternatively R₃ and R₄ form together withthe carbon atom to which they are attached a 4- to 7-membered ring, withan inorganic acid (hydrochloric acid or sulphuric acid) or an organicacid (formic acid) optionally in an alcohol containing 1 to 3 carbonatoms (methanol, ethanol or isopropanol) at a temperature of between 0°and 50° C. Preferably, formic acid is used at a temperature close to 20°C.

The acylation of the product of general formula (IV) by means of benzoylchloride or a reactive derivative of general formula (V) is carried outin an inert organic solvent chosen from esters such as ethyl acetate,isopropyl acetate or n-butyl acetate and halogenated aliphatichydrocarbons such as dichloromethane or 1,2-dichloroethane in thepresence of an inorganic base such as sodium bicarbonate or an organicbase such as triethylamine. The reaction is carried out at a temperatureof between 0° and 50° C., preferably close to 20° C.

When the radical G₁ represents a protecting group, its replacement by ahydrogen atom is carried out under the conditions described above.

The products of general formula (II) can be obtained according to one ofthe following methods:

1) by esterification of the product of general formula: ##STR5## inwhich G₁ is defined as above, by means of an acid of general formula:##STR6## in which Ar, R₁, R₃ and R₄ are defined as above, or of aderivative of this acid.

The esterification by means of an acid of general formula (VII) can becarried out in the presence of a condensing agent (carbodiimide,reactive carbonate) and an activating agent (aminopyridine) in anorganic solvent (ether, ester, ketones, nitriles, aliphatichydrocarbons, halogenated aliphatic hydrocarbons or aromatichydrocarbons) at a temperature of between -10° and 90° C.

The esterification may also be performed using the acid of generalformula (VII) in anhydride form, the procedure being carried out in thepresence of an activating agent (aminopyridine) in an organic solvent(ethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenatedaliphatic hydrocarbons or aromatic hydrocarbons) at a temperature ofbetween 0° and 90° C.

The esterification can also be performed using the acid of generalformula (VII) in halide form or in anhydride form with an aliphatic oraromatic acid, optionally prepared in situ, in the presence of a base(tertiary aliphatic amine), the procedure being carried out in anorganic solvent (ethers, esters, ketones, nitriles, aliphatichydrocarbons, halogenated aliphatic hydrocarbons or aromatichydrocarbons) at a temperature of between 0° and 80° C.

The acid of general formula (VII) can be obtained by saponification ofan ester of general formula: ##STR7## in which Ar, R₁, R₃ and R₄ aredefined as above and R₅ represents an alkyl radical containing 1 to 4carbon atoms optionally substituted by a phenyl radical.

Generally, the saponification is carried out by means of an inorganicbase (alkali metal hydroxide, carbonate or bicarbonate) inaqueous-alcoholic medium (methanol-water) at a temperature of between10° and 40° C.

The ester of general formula (VIII) can be obtained by the action of aproduct of general formula: ##STR8## in which R₃ and R₄ are defined asabove in the form of a dialkylacetal or an enol alkyl ether, on an esterof general formula: ##STR9## in which Ar, R₁ and R₃ are defined asabove, the procedure being carried out in an inert organic solvent(aromatic hydrocarbon) in the presence of a strong inorganic acid(sulphuric acid) or organic acid (p-toluenesulphonic acid optionally inthe form of a pyridinium salt) at a temperature of between 0° C. and theboiling temperature of the reaction mixture.

The ester of general formula (X) can be obtained by the action of aproduct of general formula (V) on an ester of general formula: ##STR10##in which Ar and R₅ are defined as above, the procedure being carried outin an organic solvent (ester, halogenated aliphatic hydrocarbon) in thepresence of an inorganic or organic base at a temperature of between 0°and 50° C.

The product of general formula (XI) can be obtained by reduction of anazide of general formula: ##STR11## in which Ar and R₅ are defined asabove, by means of hydrogen in the presence of a catalyst such aspalladium on carbon, the procedure being carried out in an organicsolvent (ester).

The product of general formula (XII) can be obtained by the action of anazide such as trimethylsilyl azide in the presence of zinc chloride oran alkali metal (sodium, potassium or lithium) azide in aqueous-organicmedium (water-tetrahydrofuran) at a temperature of between 20° C. andthe boiling temperature of the reaction mixture, on an epoxide ofgeneral formula: ##STR12## in which Ar and R₅ are defined as above,optionally prepared in situ.

The epoxide of general formula (XIII) can be obtained, optionally insitu, by dehydrohalogenation of a product of general formula: ##STR13##in which Ar is defined as above, Hal represents a halogen atom,preferably a bromine atom, and R₆ and R₇, which are identical ordifferent, represent a hydrogen atom or an alkyl radical containing 1 to4 carbon atoms or a phenyl radical, at least one being an alkyl radicalor a phenyl radical, by means of an alkali-metal alcoholate, optionallyprepared in situ, in an inert organic solvent such as tetrahydrofuran ata temperature of between -80° C. and 25° C.

The product of general formula (XIV) can be obtained by the action of analdehyde of general formula:

    Ar--CHO                                                    (XV)

in which Ar is defined as above, on a halide of general ##STR14## inwhich Hal, R₆ and R₇ are defined as above, anionized beforehand.

Generally, the procedure is carried out in an inert organic solventchosen from ethers (ethyl ether) and halogenated aliphatic hydrocarbons(methylene chloride) at a temperature of between -80° and 25° C., in thepresence of a tertiary amine (triethylamine) and an enolysing agent(di-n-butylboron triflate).

The product of general formula (XVI) can be obtained by the action of ahalide of a haloacetic acid, preferably bromoacetic acid bromide, on thecorresponding oxazolidinone.

The product of general formula (XI) can be obtained by hydrogenolysis ofa product of general formula: ##STR15## in which Ar and R₅ are definedas above and Ph represents an optionally substituted phenyl radical.

Generally, the hydrogenolysis is carried out by means of hydrogen in thepresence of a catalyst. More particularly, palladium on carboncontaining 1 to 10% by weight of palladium or palladium dihydroxidecontaining 20% by weight of palladium is used as catalyst.

The hydrogenolysis is carried out in an organic solvent or in a mixtureof organic solvents. It is advantageous to carry out the procedure inacetic acid optionally combined with an aliphatic alcohol containing 1to 4 carbons atom as a mixture of acetic acid-methanol at a temperatureof between 20° and 80° C.

The hydrogen necessary for the hydrogenolysis can also be provided by acompound which liberates hydrogen by chemical reaction or by thermaldecomposition (ammonium formate). It is advantageous to carry out theprocedure at a hydrogen pressure of between 1 and 50 bar.

The product of general formula (XVII) can be obtained by hydrolysis oralcoholysis of a product of general formula: ##STR16## in which Ar andPh are defined as above.

It is particularly advantageous to carry out an alcoholysis by means ofan alcohol of formula R₅ -OH in which R₅ is defined as above, theprocedure being carried out in acidic medium.

Preferably, the alcoholysis is carried out by means of methanol in thepresence of a strong inorganic acid such as hydrochloric acid at atemperature close to the reflux temperature of the reaction mixture.

The product of general formula (XVIII) can be obtained by saponificationof an ester of general formula: ##STR17## in which Ar and Ph are definedas above and R₈ represents an alkyl, phenylalkyl or phenyl radical,followed by separation of the 3R, 4S diastereoisomer of general formula(XVII) from the other diastereoisomers.

Generally, the saponification is carried out by means of an inorganic ororganic base such as ammonium hydroxide, lithium hydroxide, sodiumhydroxide or potassium hydroxide in a suitable solvent such as amethanol-water or tetrahydrofuran-water mixture at a temperature ofbetween -10° C. and 20° C.

The separation of the 3R, 4S diastereoisomer can be carried out byselective crystallization from a suitable organic solvent such as ethylacetate.

The product of general formula (XIX) can be obtained by cycloaddition ofan imine of general formula: ##STR18## in which Ar and Ph are defined asabove, onto an acid halide of general formula: ##STR19## in which R₈ isdefined as above and Y represents a halogen atom such as a bromine orchlorine atom.

Generally, the reaction is carried out at a temperature of between 0°and 50° C. in the presence of a base chosen from aliphatic tertiaryamines (triethylamine) or pyridine in an organic solvent chosen fromoptionally halogenated aliphatic hydrocarbons (methylene chloride orchloroform) and aromatic hydrocarbons (benzene, toluene or xylenes).

The product of general formula (XX) can be obtained under conditionsanalogous to those described by M. Furukawa et al., Chem. Pharm. Bull.,25 (1), 181-184 (1977).

The product of general formula (VI) can be obtained by the action of analkali metal halide (sodium iodide or potassium fluoride) or an alkalimetal azide (sodium azide) of a quaternary ammonium salt or an alkalimetal phosphate, on a baccatin III or 10-deacetylbaccatin III derivativeof general formula: ##STR20## in which G₁ is defined as above.

Generally, the reaction is carried out in an organic solvent chosen fromethers (tetrahydrofuran, diisopropyl ether, methyl t-butyl ether) andnitriles (acetonitrile), alone or in the form of a mixture, at atemperature of between 20° C. and the boiling temperature of thereaction mixture.

The product of formula (XXII) in which G₁ represents a hydrogen atom oran acetyl, alkoxyacetyl or alkyl radical can be obtained by the actionof a trifluoromethanesulphonic acid derivative such as the anhydride orN-phenyltrifluoromethanesulphonimide, on baccatin III or10-deacetylbaccatin III, which can be extracted according to knownmethods from yew leaves (Taxus baccata), optionally followed byprotection in position 10, it being understood that in order to obtain aproduct of general formula (XXII) in which G₁ represents an alkoxyacetylor alkyl radical, it is necessary to treat beforehand the10-deacetylbaccatin III protected in position 7, preferably with asilylated radical, with an alkoxy acetic acid halide or with an alkylhalide.

Generally, the reaction of a trifluoromethanesulphonic acid derivativeis carried out in an inert organic solvent (optionally halogenatedaliphatic hydrocarbons, or aromatic hydrocarbons) in the presence of anorganic base such as an aliphatic tertiary amine (triethylamine) orpyridine, at a temperature of between -50° and +20° C.

Generally, the introduction of an alkoxyacetyl group is carried out bytreating the protected 10-deacetylbaccatin III with an alkoxyacetic acidhalide, the procedure being carried out in a basic organic solvent suchas pyridine at a temperature close to 20° C.

Generally, the introduction of an alkyl radical is carried out bytreating the 10-deacetylbaccatin III, protected and metallized inposition 10, by means, for example, of an alkali metal hydride (sodiumhydride) or a metallic alkylide (butyllithium), with an alkyl halide. 2)by the action of an alkali metal halide (sodium iodide or potassiumfluoride) or an alkali metal azide (sodium azide) or a quaternaryammonium salt or an alkali metal phosphate on a product of generalformula: ##STR21## in which Ar, R₁, R₃, R₄ and G₁ are defined as above.

Generally, the reaction is carried out in an organic solvent chosen fromethers (tetrahydrofuran, diisopropyl ether or methyl t-butyl ether) andnitriles (acetonitrile), alone or in the form of a mixture, at atemperature of between 20° C. and the boiling temperature of thereaction mixture.

The product of general formula (XXIII) can be obtained by the action ofa trifluoromethanesulphonic acid derivative such as the anhydride orN-phenyltrifluoromethanesulphonimide on a taxoid of general formula:##STR22## in which Ar, R₁, R₃, R₄ and G₁ are defined as above.

Generally, the reaction is carried out in an inert organic solvent(optionally halogenated aliphatic hydrocarbons, or aromatichydrocarbons) in the presence of an organic base such as an aliphatictertiary amine (triethylamine) or pyridine, at a temperature of between-50° C. and +20° C.

The taxoid of general formula (XXIV), in which G₁ represents a hydrogenatom or an acetyl radical, can be obtained from a product of generalformula: ##STR23## in which Ar, R₁, R₃, and R₄ are defined as above, G'₁represents a hydroxy-protecting group and G'₂ represents an acetyl,alkoxyacetyl or alkyl radical or a hydroxy-protecting group, byreplacement of the protecting groups G'₁ and optionally G'₂ by hydrogenatoms.

The radicals G'₁ and G'₂, when they represent a hydroxy-protectinggroup, are preferably 2,2,2-trichloroethoxycarbonyl or2-(2-trichloromethylpropoxy)carbonyl radicals or trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl or triarylsilyl radicals in which thealkyl portions contain 1 to 4 carbon atoms and the aryl portions arepreferably phenyl radicals, it being possible, in addition, for G'₂ torepresent an alkoxyacetyl radical.

When G'₁ and G'₂ represent a 2,2,2-trichloromethylpropoxy)carbonyl or2-(2-trichloromethylpropoxy)carbonyl radical, the replacement of theprotecting groups by hydrogen atoms is carried out using zinc,optionally combined with copper, in the presence of acetic acid at atemperature of between 20° and 60° C. or by means of an inorganic ororganic acid such as hydrochloric acid or acetic acid in solution in analiphatic alcohol containing 1 to 3 carbon atoms or an aliphatic estersuch as ethyl acetate, isopropyl acetate or n-butyl acetate in thepresence of zinc optionally combined with copper.

When G'₁ represents a silylated radical and G'₂ represents an acetyl,alkoxyacetyl or alkyl radical, the replacement of the protecting groupG'₁ by a hydrogen atom can be carried out by means of, for example,gaseous hydrochloric acid in ethanolic solution at a temperature closeto 0° C., under conditions which are without effect on the rest of themolecule.

When G'₂ represents an alkoxyacetyl radical, its optional replacement bya hydrogen atom is carried out by treatment in alkaline medium or by theaction of a zinc halide under conditions which do not affect the rest ofthe molecule. Generally, the alkaline treatment is carried out by theaction of ammonia in aqueous-alcoholic medium, at a temperature close to20° C. Generally, the treatment with a zinc halide, preferably zinciodide, is carried out in methanol at a temperature close to 20° C.

The product of general formula (XXV) can be obtained under theconditions described in international application PCT/WO 9209589.

The new derivatives of general formula (I) can also be obtained byesterification of a product of general formula (VI) by means of an acidof general formula: ##STR24## in which Ar and R₁ are defined as aboveand G₃ represents a hydroxy-protecting group chosen from methoxymethyl,1-ethoxyethyl, benzyloxymethyl, (δ-trimethylsilyloxy)methyl,tetrahydropyranyl, 2,2,2-trichloroethoxymethyl,2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonylradicals or CH₂ -Ph radicals in which Ph represents a phenyl radicaloptionally substituted by one or more atoms or radicals, which areidentical or different, chosen from halogen atoms and alkyl radicalscontaining 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4carbon atoms, or an activated derivative of this acid, to give a productof general formula: ##STR25## in which Ar, R₁, G₁, G₂ and G₃ are definedas above, followed by the replacement of the protecting groups G₁, G₂and G₃ by hydrogen atoms to give a product of general formula (I).

The esterification can be performed under the conditions described abovefor the esterification of the product of general formula (VI) by meansof an acid of general formula (VII).

The replacement of the protecting groups G₁ and G₃ of the product ofgeneral formula (XXVII) by a hydrogen atom is carried out by treatmentwith zinc, optionally combined with copper, in the presence of aceticacid at a temperature of between 30° and 60° C. or by means of aninorganic or organic acid such as hydrochloric acid or acetic acid insolution in an aliphatic alcohol containing 1 to 3 carbon atoms or analiphatic ester such as ethyl acetate, isopropyl acetate or n-butylacetate in the presence of zinc optionally combined with copper, when G₁and G₃ represent a 2,2,2-trichloroethoxycarbonyl or2-(2-trichloromethylpropoxy)carbonyl radical. The replacement of theprotecting group G₃, when it represents a silylated radical or an acetalresidue, can be carried out by treatment in acidic medium such as forexample hydrochloric acid in solution in an aliphatic alcohol containing1 to 3 carbon atoms (methanol, ethanol, propanol or isopropanol) oraqueous hydrofluoric acid at a temperature of between 0° and 40° C.,when it represents an acetal residue, the replacement of the protectinggroup G₁ then being carried out under the conditions described above.When G₃ represents a group --CH₂ --Ph, the replacement of thisprotecting group with a hydrogen atom can be carried out byhydrogenolysis in the presence of a catalyst.

The acid of general formula (XXVI) can be obtained by saponification ofan ester of general formula: ##STR26## in which Ar, R₁, R₃ and G₃ aredefined as above.

Generally, the saponification is carried out by means of an inorganicbase (alkali metal hydroxide, carbonate or bicarbonate) inaqueous-alcoholic medium (methanol-water) at a temperature of between10° and 40° C.

The ester of general formula (XXVIII) can be obtained according to theusual methods for the preparation of ethers, and more particularlyaccording to the procedures described by J-N. DENIS et al., J. Org.Chem., 51, 46-50 (1986), from a product of general formula (XI).

The new products of general formula (I) obtained using the proceduresaccording to the invention can be purified according to known methodssuch as crystallization or chromatography.

The products of general formula (I) have remarkable biologicalproperties.

In vitro, measurement of the biological activity is carried out ontubulin extracted from pig brain by the method of M. L. Shelanski et al.Proc. Natl. Acad. Sci. USA, 70, 765-768 (1973). The study of thedepolymerization of the microtubules into tubulin is carried outaccording to the method of G. Chauviere et al., C. R. Acad. Sci., 293,serie II, 501-503 (1) In this study, the products of general formula (I)proved at least as active as taxol and Taxotere.

In vivo, the products of general formula (I) proved active in micegrafted with the B16 melanoma at doses of between 1 and 10 mg/kgintraperitoneally, as well as on other liquid or solid tumours.

The new compounds have anti-tumor properties, more particularly,activity against tumors which are resistant to Taxol® and Taxotere®.Such tumors include, for example, colon tumors which have an elevatedexpression of mdr 1 gene (multi- drug resistant gene). Multi-drugresistance is the usual term relating to the resistance by a tumoragainst various compounds having differing structures and mechanisms ofaction. Taxoids are generally known to be highly recognized byexperimental tumors such as P388/DOX, a P388 murine leukemia cell lineselected for doxorubicin (DOX) resistance, which express mdr 1. The newcompounds according to the present invention are less recognized byP388/DOX. More particularly, the new compounds are less recognized thanTaxotere® by mdr 1.

In particular, it has been found that the new compounds of the presentinvention including the compounds of example 1, example 2 and example 3have better multi-drug resistance properties than Taxol® and Taxotere®.Additionally it has surprisingly been found that the compound of example3 has substantially better multi-drug resistance properties than thecompounds of example 1 and example 2.

The following examples illustrate the present invention.

EXAMPLE 1

A solution of 2.01 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-7β,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylatein 20 cm³ of formic acid is stirred for 4 hours at a temperature closeto 20° C. and then concentrated to dryness under reduced pressure (0.27kPa) at 40° C. The foam obtained is dissolved in 100 cm³ ofdichloromethane and the solution obtained is supplemented with 20 cm³ ofa saturated aqueous sodium hydrogen carbonate solution. The aqueousphase is separated after settling has taken place and extracted with 20cm³ of dichloromethane. The organic phases are pooled, dried overmagnesium sulphate, filtered and then concentrated to dryness underreduced pressure (2.7 kPa) at 40° C. 1.95 g of a white foam are obtainedwhich are purified by chromatography on 200 g of silica (0.063-0.2 mm)contained in a column 7 cm in diameter, eluting with adichloromethane-methanol mixture (98-2 by volume) and collecting 30 cm³fractions. The fractions containing only the desired product are pooledand concentrated to dryness under reduced pressure (0.27 kPa) at 40° C.for 2 hours. 1.57 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-7β,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(2R,3S)-3-amino-2-hydroxy-3-phenylpropionate are obtained in the form ofa white foam.

To a solution of 400 mg of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-7β,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(2R,3S)-3-amino-2-hydroxy-3-phenylpropionate in 1 cm³ ofdichloromethane, kept under an argon atmosphere, are added 60 mg ofsodium hydrogen carbonate and then, dropwise, at a temperature close to20° C., a solution of 0.16 g of di-tert-butyl dicarbonate in 1 cm³ ofdichloromethane. The solution obtained is stirred for 64 hours at atemperature close to 20° C. and then supplemented with a mixture of 5cm³ of distilled water and 10 cm³ of dichloromethane. The organic phaseis washed with three times 2 cm³ of distilled water. The organic phaseis dried over magnesium sulphate, filtered and then concentrated todryness under reduced pressure (2.7 kPa) at 40° C. 317 mg of a whitefoam are thus obtained which are purified by chromatography on 30 g ofsilica (0.063-0.2 mm) contained in a column 3 cm in diameter, elutingwith a dichloromethane-methanol mixture (95-5 by volume) and collecting5 cm³ fractions. The fractions containing only the desired product arepooled and concentrated to dryness under reduced pressure (0.27 kPa) at40° C. for 2 hours. 161 mg of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-7β,8β-methylene-9-oxo-19-nor-11taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate are thusobtained in the form of a white foam whose characteristics are thefollowing:

specific rotation: [α]_(D) ²⁰ =-17° (c=0.482; methanol)

proton NMR spectrum: (400 MHz; CDCl₃ ; temperature of 323K; δ in ppm;coupling constants J in Hz):1.21 (s, 3H: --CH₃ 16 or 17); 1.28 (s, 3H:--CH₃ 16 or 17); 1.34 [s, 9H: --C(CH₃)₃ ]; from 1.30 to 1.50 (mt, 1H:--H7); 1.80 and 2.36 (2 mt, 1H each: --CH₂ -- of cyclopropane); 1.88 (s,3H: --CH₃ 18); 2.13 [mt, 1H: --(CH) --H 6]; 2.26 [dd, 1H, J=15 to 8.5:--(CH) --H 14]; 2.35 (s, 3H: --COCH₃); from 2.35 to 2.50 [mt, 2H: --(CH)--H 14 and --(CH) --H 6]; 3.21 (d, 1H, J=4: --OH 2'); 4.08 [d, 1H, J=8:--(CH) --H 20]; 4.16 (d, 1H, J=7: --H 3); 4.18 (s, 1H, --OH10); 4.31 [d,1H, J=8: --(CH) --H 20]:4.61 (dd, 1H, J=4 and 2: --H 2'); 4.74 (d, 1H,J=4: --H 5); 5.00 (s, 1H: --H 10); 5.26 (dd, 1H, J=9 and 2: --H 3');5.33 (d, 1H, J=9: --NH 3'); 5.69 (d, 1H, J=7: --H 2); 6.29 (d, 1H,J=8.5: --H 13); from 7.30 to 7.50 [mt, 5H: --C₆ H₅ in 3' (--H 2 to --H6); 7.51 [t, 2H, J=7.5: --OCOC₆ H₅ (--H 3 and H 5)]; 7.60 [t, 1H, J=7.5:--OCOC₆ H₅ (--H 4)]; 8.14 [d, 2H, J=7.5: --OCOC₆ H₅ (--H 2 and H 6)].

The4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-7β,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylatecan be prepared in the following manner:

To a solution of 2.5 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-9-oxo-7β-trifluoromethanesulphonate-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylatein 25 cm³ of anhydrous acetonitrile and 3 cm³ of anhydroustetrahydrofuran, kept under an argon atmosphere, are added 2.5 g ofsodium azide. The reaction mixture is heated for 2 hours, with stirringand under an argon atmosphere at a temperature close to 80° C., thencooled to a temperature close to 20° C. and supplemented with 30 cm³ ofdistilled water. The aqueous phase is separated by decantation and thenextracted with 20 cm³ of dichloromethane. The combined organic phasesare dried over magnesium sulphate, filtered and then concentrated todryness under reduced pressure (2.7 kPa) at 40° C. 2.44 g of a yellowfoam are thus obtained which are purified by chromatography on 300 g ofsilica (0.063-0.2 mm) contained in a column 8 cm in diameter, elutingwith a dichloromethane-ethyl acetate mixture (90-10 by volume) andcollecting 60 cm³ fractions. Fractions 47 to 70 are pooled andconcentrated to dryness under reduced pressure (0.27 kPa) at 40° C. for2 hours. 2.01 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-7β,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylateare thus obtained in the form of a white foam.

The4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-9-oxo-7β-trifluoromethanesulphonate-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylatecan be prepared in the following manner:

To a solution of 2.86 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,7β,10β-trihydroxy-9-oxo-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylatein 29 cm³ of anhydrous dichloromethane, kept under an argon atmosphere,are added 0.955 cm³ of pyridine and 50 mg of powdered activated 4 Åmolecular sieve. The reaction mixture is cooled to a temperature closeto -35° C., slowly supplemented with 0.85 cm³ oftrifluoromethanesulphonic anhydride, stirred at a temperature close to-5° C. for 15 minutes and supplemented with 10 cm³ of distilled water.After filtration on sintered glass provided with celite and rinsing offthe sintered glass with 3 times 10 cm³ of a methanol-dichloromethanemixture (10-90 by volume), the aqueous phase is separated after settlinghas taken place and extracted with twice 10 cm³ of dichloromethane. Theorganic phases are pooled, dried over magnesium sulphate, filtered andthen concentrated to dryness under reduced pressure (2.7 kPa) at 40° C.3.87 g of a white foam are obtained which are purified by chromatographyon 400 g of silica (0.063-0.2 mm) contained in a column 10 cm indiameter, eluting with a dichloromethane-ethyl acetate gradient (from97.5-2.5 to 90-10 by volume) and collecting 80 cm³ fractions. Thefractions containing only the desired product are pooled andconcentrated to dryness under reduced pressure (0.27 kPa) at 40° C. for2 hours. 3.0 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-9-oxo-7β-trifluoromethanesulphonate-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylateare thus obtained in the form of a white foam.

The4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,7β,10β-trihydroxy-9-oxo-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylatecan be prepared in the following manner:

A solution of 24.35 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-9-oxo-7β,10β-[bis(2,2,2-trichloroethoxy)carbonyloxy]-1β-hydroxy-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylatein a mixture of 130 cm³ of ethyl acetate and 46.5 cm³ of acetic acid isheated, with stirring and under an argon atmosphere up to a temperatureclose to 60° C. and then supplemented with 40 g of zinc powder. Thereaction mixture is then stirred for 30 minutes at 60° C. and thencooled to a temperature close to 20° C. and filtered on sintered glassprovided with celite. The sintered glass is washed with 100 cm³ of amethanol-dichloromethane mixture (20-80 by volume); the filtrates arepooled and then concentrated to dryness under reduced pressure (0.27kPa) at a temperature close to 40° C.

The residue is supplemented with 500 cm³ of dichloromethane. The organicphase is washed with twice 50 cm³ of a saturated aqueous sodium hydrogencarbonate solution and then with 50 cm³ of distilled water. The aqueousphases obtained after settling has taken place and pooled are extractedwith twice 30 cm³ of dichloromethane. The organic phases are pooled,dried over magnesium sulphate, filtered and then concentrated to drynessunder reduced pressure (2.7 kPa) at 40° C. 19.7 g of a white foam areobtained which are purified by chromatography on 800 g of silica(0.063-0.2 mm) contained in a column 10 cm in diameter, eluting with adichloromethane-methanol gradient (from 100-0 to 97-3 by volume) andcollecting 80 cm³ fractions. The fractions containing only the desiredproduct are pooled and concentrated to dryness under reduced pressure(0.27 kPa) at 40° C. for 2 hours. 16.53 g of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,7β,10β-trihydroxy-9-oxo-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylatein the form of a white foam.

The4-acetoxy-2α-benzoyloxy-5β,20-epoxy-9-oxo-7β,10β-[bis(2,2,2-trichloroethoxy)carbonyloxy]-1β-hydroxy-11-taxen-13α-yl(4S,5R)-3tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylatecan be prepared according to the method described in internationalapplication PCT WO 9209589.

EXAMPLE 2

To a solution of 550 mg of4α,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(2R,3S)-3-amino-2-hydroxy-3-phenylpropionate are added 45 cm³ ofdistilled water, 45 cm³ of a saturated aqueous sodium hydrogen carbonatesolution and then, dropwise, at a temperature close to 20° C., 0.096 cm³of benzoyl chloride. The mixture obtained is stirred for 10 minutes at atemperature close to 20° C. After settling has taken place, the aqueousphase is extracted with twice 30 cm³ of ethyl acetate. The combinedorganic phases are dried over magnesium sulphate, filtered and thenconcentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 670mg of a white foam are thus obtained which are purified bychromatography at atmospheric pressure on 50 g of silica (0.063-0.2 mm)contained in a column 2.5 cm in diameter, eluting with amethanol-dichloromethane mixture (1-99 then 2.5-97.5 by volume) andcollecting 10 cm³ fractions. The fractions containing only the desiredproduct are pooled and concentrated to dryness under reduced pressure(2.7 kPa) at 40° C. 610 mg of a white foam are thus obtained. A sampleof 300 mg is purified by preparative chromatography on 12 thin-layersilica plates (Kieselgel 60F254, Merck; thickness 0.25 mm), eluting witha methanol-dichloromethane mixture (3-97 by volume). After elution ofthe zone corresponding to the main product with amethanol-dichloromethane mixture (10-90 by volume) and then evaporationof the solvents under reduced pressure (0.27 kPa) at a temperature closeto 40° C., 155.2 mg of4α,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(2R,3S)-3-benxoylamino-2-hydroxy-3-phenylpropionate are obtained in theform of a white foam whose characteristics are the following:

specific rotation: [α]_(D) ²⁰ =-30.5° (c=0.491; methanol)

proton NMR spectrum: (300 MHz; CDCl₃ ; δ in ppm; coupling constants J inHz):1.27 (s, 3H: --CH₃ 16 or 17); 1.30 (s, 3H: --CH₃ 16 or 17); 1.40(mt, 1H: --H7); 1.62 and 2.25 (q and m, 1H each: CH₂ -- ofcyclopropane); 1.85 (s, 3H: --CH₃ 18); 1.96 (s, 1H: --OH in 1); 2.05 and2.48 (d and m, 1H each: --CH₃ -- in 6); 2.24 (s, 3H: --COCH₃ in 10);2.28 and 2.50 (m, 1H each: --CH₃ in 14); 2.45 (s, 3H: --COCH₃ in 4);3.52 (d, 1H: --OH in 2'); 4.10 and 4.35 (d, 1H each: --CH₂ in 20); 4.11(d, 1H: --H3); 4.77 (broad d, 1H: --H5); 4.82 (dd, 1H: --H2'); 5.70 (d,1H: --H in 2); 5.84 (dd, 1H: --H3'); 6.30 (broad t, 1H: --H13); 6.36 (s,1H: --H10); 7.00 (d, 1H: --CONH--); from 7.35 to 8.30 (m, 15H: --C₆ H₅in 3', --OCOC₆ H₃ and NHCOC₆ H₅).

The4α,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(2R, 3S)-3-amino-2-hydroxy-3-phenylpropionate can be prepared bycarrying out the procedure under the conditions described in Example 1for the preparation of4-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-7β,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(2R,3S)-3-amino-2-hydroxy-3-phenylpropionate. Thus, starting with 1.6 gof4α,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidincarboxylate,1.14 g of4α,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,8β-methylene-9-oxo-19-nor-11-taxen-13α-ylare obtained in the form of a white foam.

The4α,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidincarboxylatecan be prepared under the conditions described in Example 1 for thepreparation of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-7β,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate.Thus, starting with 2.2 g of4α,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-9-oxo-7β-trifluoromethanesulphonate-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidincarboxylate,1.62 g of4α,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidincarboxylateare obtained in the form of a white foam.

The4α,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-9-oxo-7β-trifluoromethanesulphonate-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidincarboxylatecan be prepared under the conditions described in Example 1 for thepreparation of4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,10β-dihydroxy-9-oxo-7β-trifluoromethanesulphonate-19-nor-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidincarboxylate.Thus, starting with 2.4 g of4α,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1β,7β-dihydroxy-9-oxo-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidincarboxylate,2.46 g of4α,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-9-oxo-7β-trifluoromethanesulphonate-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidincarboxylateare obtained in the form of a white foam.

The4α,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1β,7β-dihydroxy-9-oxo-11-taxen-13α-yl(4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidincarboxylatecan be prepared under the conditions described in InternationalApplication PCT WO 9209589.

EXAMPLE 3

To a solution of 550 mg of4α,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(2R,3S)-3-amino-2-hydroxy-3-phenylpropionate in 1 cm³ ofdichloromethane, kept under an argon atmosphere, are added 76 mg ofsodium hydrogen carbonate and then, dropwise, at a temperature close to20° C., a solution of 197 mg of di-tert-butyl dicarbonate in 1 cm³ ofdichloromethane. The solution obtained is stirred for 15 hours at atemperature close to 20° C. and then supplemented with a mixture of 5cm³ of distilled water and 10 cm³ of dichloromethane. The aqueous phaseis extracted with 5 cm³ of dichloromethane. The combined organic phasesare dried over magnesium sulphate, filtered and then concentrated todryness under reduced pressure (2.7 kPa) at 40° C. 780 mg of a whitefoam are thus obtained which are purified by chromatography atatmospheric pressure on 50 g of silica (0.063-0.2 mm) contained in acolumn 2.5 cm in diameter, eluting with a methanol-dichloromethanemixture (1-99 then 2.5-97.5 by volume) and collecting 10 cm³ fractions.The fractions containing only the desired product are pooled andconcentrated to dryness under reduced pressure (2.7 kPa) at 40° C. 660mg of a white foam are thus obtained. A sample of 300 mg is purified bypreparative chromatography on 12 thin-layer silica plates (Kieselgel60F254, Merck; thickness 0.25 mm), eluting with amethanol-dichloromethane mixture (4-96 by volume). After elution of thezone corresponding to the main product with a methanol-dichloromethanemixture (10-90 by volume) and then evaporation of the solvents underreduced pressure (0.27 kPa) at a temperature close to 40° C., 159.7 mgof4α,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1β-hydroxy-7β,8β-methylene-9-oxo-19-nor-11-taxen-13α-yl(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate areobtained in the form of a white foam whose characteristics are thefollowing:

specific rotation: [α]_(D) ²⁰ =-34° (c=0.564; methanol)

proton NMR spectrum: (400 MHz; CDCl₃ ; δ in ppm; coupling constants J inHz): 1.28 (s, 3H: --CH₃ 16 or 17); 1.30 [s, 9H: --C(CH₃)₃ ]; 1.38 (mt,1H: --H7); 1.60 (s, 3H; --CH₃ 16 or 17); 1.68 and 2.25 (t and m, 1Heach; CH₃ -- of cyclopropane); 1.85 (s, 3H: --CH₃ 18); 2.10 and 2.45 (dand td, 1H each: --CH₃ -- in 6); 2.23 (s, 3H: --COCH₃ in 10); 2.22 and2.40 (m, 1H each: --CH₃ -- in 14); 2.40 (s, 3H: --COCH₃ in 4); 3.28 (d,1H: --OH in 2'); 4.05 and 4.22 (d, 1H each: --CH₃ -- in 20); 4.10 (d,1H: --H3); 4.62 (broad s, 1H: --H2'); 4.73 (d, 1H: --H5); 5.29 (broad d,1H: --H3'); 5.37 (d, 1H: --CONH--); 5.67 (d, 1H: --H in 2); 6.28 (broadt, 1H: --H13); 6.33 (s, 1H: --H10); from 7.30 to 7.45 (mt, 5H: --C₆ H₅in 3'); 7.51 [t, 2H: --OCOC₆ H₅ (--H3 and --H5)]; 7.61 [t, 1H: --OCOC₆H₅ (--H4)]; 8.17 [d, 2H: --OCOC₆ H₅ (--H2 and --H6)].

EXAMPLE 4

To a solution of 100 mg of 10-deacetylbaccatin III in a mixture of 3 cm³of tetrahydrofuran and 0.05 cm³ of pyridine cooled to a temperatureclose to -78° C. and kept under an argon atmosphere, is added, dropwise,0.09 cm³ of trifluoromethanesulphonic anhydride. The temperature isallowed to rise slowly to a temperature close to 0° C. overapproximately one hour, than up to a temperature close to 20° C. overapproximately one hour. After 2 hours at a temperature close to 20° C.,200 mg of tetrabutylammonium iodide are added, then the solution isheated at the boiling temperature of the solvent for 15 hours. Aftercooling to a temperature close to 20° C., 10 cm³ of ethyl acetate andthen 1 cm³ of distilled water are added. After separation after settlinghas taken place, the organic phase is dried over magnesium sulphate,filtered and concentrated to dryness under reduced pressure (2.7 kPa) at40° C. 116 mg of a yellow oil are thus obtained which are purified bychromatography at atmospheric pressure on 30 g of silica (0.063-0.2 mm)contained in a column 2.5 cm in diameter, eluting with an ethylacetate-dichloromathane mixture, with an elution gradient from 0-100 to80-20 by volume. The fractions containing the desired product are pooledand concentrated to dryness under reduced pressure (0.27 kPa) at 40° C.10.3 mg of 10-deacetyl-7β, 8β-methylene-19-norbaccatin III are thusobtained in the form of a white foam whose characteristics are thefollowing:

proton NMR spectrum: (400 MHz; CDCl₃ ; δ in ppm; coupling constants J inHz): 1:14 (s, 3H: --CH₃ in 16 or 17); 1.42 (mt, 1H: --H in 7); 1.76 and2.31 (t and m, 1H each; CH₃ of cyclopropane); 2.07 (s, 3H; --CH₃ in 18);2.15 and 2.50 (broad d and td, 1H each: CH₃ -- in 6); 2.30 (s, 3H:--COCH₃ in 4); 2.28 and 2.35 (m, 1H each: --CH₂ in 14); 4.11 and 4.37(d, 1H each: --CH₃ in 20); 4.28 (d, 1H: --H3 in 3); 4.79 (d,, 1H: --H in5); 4.88 (broad t, 1H: --H in 13); 5.09 (s, 1H: --H in 10); 5.66 (d, 1H:--H in 2); 7.51 [t, 2H: --OCOC₆ H₅ (--H in 3 and 5)]; 7.61 [t, 1H:--OCOC₆ H₅ (--H in 4)]; 8.17 [d, 2H: --OCOC₆ H₅ (--H in 2 and 6)].

¹³ C NMR spectrum: (100 MHz; CDCl₃ ; δ in ppm; uncoupled; s=singlet,d=doublet; t=triplet; q=quadruplet); 15 (q, C18); 16.5 (t, C19); 20 and27 (q, C16 and C17); 22.5 (q, --COCH₃); 26.5 (t, C6); 33 (d, C7); 35 (s,C8); 39 (d, C3); 39.5 (t, C14); 43 (s, C15); 68 (d, C13 ); 76 (t, C20);76.2 (d, C10); 79.5 (s, C1); 80 (s, C4); 81 (d, C2); 85 (d, C5); 129 (d,C2: --OCOC₆ H₅); 130 (s, C1 of --OCOC₆ H₃); 130.5 (d, C3 of --OCOC₆ H₅);134 (d, C4 of --OCOC₆ H₅); 136 (s, C11); 143 (s, C12); 168 (s, --OCOC₆H₅); 171 (s, --COCH₃); 210 (s, C9).

The new products of general formula (I) manifest a significantinhibitory activity with respect to abnormal cell proliferation andpossess therapeutic properties which permit the treatment of patientshaving pathological conditions associated with abnormal cellproliferation. The pathological conditions include the abnormal cellproliferation of malignant or nonmalignant cells of various tissuesand/or organs, comprising, with no limitation being implied, muscle,bone or connective tissues, the skin, brain, lungs, sex organs, thelymphatic or renal systems, mammary or blood cells, liver, the digestivetract, pancreas and thyroid or adrenal glands. These pathologicalconditions can also include psoriasis, solid tumours, cancers of theovary, breast, brain, prostate, colon, stomach, kidney or testicles,Kaposi's sarcoma, cholangioma, chorioma, neuroblastoma, Wilms' tumour,Hodgkin's disease, melanomas, multiple myelomas, lymphatic leukaemiasand acute or chronic granulocytic lymphomas. The new products accordingto the invention are particularly useful for the treatment of cancer ofthe ovary. The products according to the invention can be used toprevent or retard the appearance or reappearance of the pathologicalconditions or to treat these pathological conditions.

The products according to the invention can be administered to a patientin various forms adapted to the chosen route of administration which ispreferably the parenteral route. Parenteral administration comprisesintravenous, intraperitoneal, intramuscular or subcutaneousadministrations. Intraperitoneal or intravenous administration is moreparticularly preferred.

The present invention also comprises pharmaceutical compositionscontaining at least one product of general formula (I) in a sufficientquantity adapted to use in human or veterinary therapy. The compositionscan be prepared according to the customary methods, using one or morepharmaceutically acceptable adjuvants, carriers or excipients. Suitablecarriers include diluents, sterile aqueous media and various nontoxicsolvents. Preferably, the compositions are provided in the form ofaqueous solutions or suspensions, of injectable solutions which maycontain emulsifying agents, colorants, preservatives or stabilizers.

The choice of adjuvants or excipients may be determined by thesolubility and the chemical properties of the product, the particularmode of administration and good pharmaceutical practice.

For parenteral administration, aqueous or nonaqueous sterile solutionsor suspensions are used. For the preparation of nonaqueous solutions orsuspensions, natural vegetable oils such as olive oil, sesame oil orparaffin oil or injectable organic esters such as ethyl oleate can beused. The aqueous sterile solutions may consist of a solution of apharmaceutically acceptable salt in solution in water. The aqueoussolutions are suitable for intravenous administration in so far as thepH is appropriately adjusted and isotonicity is achieved, for example,with a sufficient quantity of sodium chloride or glucose. Thesterilization can be performed by heating or by any other means whichdoes not adversely affect the composition.

It is clearly understood that all the products entering into thecompositions according to the invention should be pure and nontoxic forthe quantities used.

The compositions may contain at least 0.01% of therapeutically activeproduct. The quantity of active product in a composition is such that asuitable dosage can be prescribed. Preferably, the compositions areprepared such that a single dose contains about 0.01 to 1000 mg ofactive product for parenteral administration.

The therapeutic treatment can be performed concurrently with othertherapeutic treatments including antineoplastic drugs, monoclonalantibodies, immunotherapies or radiotherapies or biological responsemodifiers. The response modifiers include, with no limitation beingimplied, lymphokines and cytokines such as interleukins, interferons (α,β or δ) and TNF. Other chemotherapeutic agents which are useful in thetreatment of disorders caused by abnormal proliferation of cellsinclude, with no limitation being implied, alkylating agents likenitrogen mustards such as mechloretamine, cyclophosphamide, melphalanand chlorambucil, alkyl sulphonates such as busulfan, nitrosoureas suchas carmustine, lomustine, semustine and streptozocin, triazenes such asdacarbazine, antimetabolites such as folic acid analogues likemethotrexate, pyrimidine analogues such as fluorouracil and cytarabine,purine analogues such as mercaptopurine and thioguanine, naturalproducts like vinca alkaloids such as vinblastine, vincristine andvindesine, epipodophyllotoxins such as etoposide and teniposide,antibiotics such as dactinomycin, daunorubicin, doxorubicin, bleomycin,plicamycin and mitomycin, enzymes such as L-asparaginase, various agentssuch as coordination complexes of platinum like cisplatin, substitutedureas like hydroxyurea, methylhydrazine derivatives such asprocarbazine, adrenocortical suppressants such as mitotane andaminoglutethymide, hormones and antagonists such asadrenocorticosteroids such as prednisone, progestins such ashydroxyprogesterone caproate, methoxyprogesterone acetate and megestrolacetate, oestrogens such as diethylstilbestrol and ethynylestradiol,antioestrogens such as tamoxifen, and androgens such as testosteronepropionate and fluoxymesterone.

The doses used for carrying out the methods according to the inventionare those which permit a prophylactic treatment or a maximum therapeuticresponse. The doses vary according to the form of administration, theparticular product selected and the characteristics specific to thesubject to be treated. In general, the doses are those which aretherapeutically effective for the treatment of disorders caused byabnormal cell proliferation. The products according to the invention canbe administered as often as necessary to obtain the desired therapeuticeffect. Some patients may respond rapidly to relatively high or lowdoses, and then require low or zero maintenance doses. Generally, lowdoses will be used at the beginning of the treatment and, if necessary,increasingly higher doses will be administered until an optimum effectis obtained. For other patients, it may be necessary to administermaintenance doses 1 to 8 times per day, preferably 1 to 4 timesaccording to the physiological needs of the patient considered. It isalso possible that for certain patients it may be necessary to use onlyone to two daily administrations.

In man, the doses are generally between 0.01 and 200 mg/kg. Forintraperitoneal administration, the doses will generally be between 0.1and 100 mg/kg and, preferably, between 0.5 and 50 mg/kg and, still morespecifically, between 1 and 10 mg/kg. For intravenous administration,the doses are generally between 0.1 and 50 mg/kg and, preferably,between 0.1 and 5 mg/kg and, still more specifically, between 1 and 2mg/kg. It is understood that, in order to choose the most appropriatedosage, account should be taken of the route of administration, thepatient's weight, his general state of health, his age and all factorswhich may influence the efficacy of the treatment.

The following example illustrates a composition according to theinvention.

EXAMPLE

40 mg of the product obtained in Example 1 are dissolved in 1 cm³ ofEmulphor EL 620 and 1 cm³ of ethanol and then the solution is diluted byaddition of 18 cm³ of physiological saline.

The composition is administered by perfusion for 1 hour by introductioninto physiological saline.

Although the invention has been described in conjunction with specificembodiments, it is evident that many alternatives and variations will beapparent to those skilled in the art in light of the foregoingdescription. Accordingly, the invention is intended to embrace all ofthe alternatives and variations that fall within the spirit and scope ofthe appended claims. The above references are hereby incorporated byreference.

We claim:
 1. A process for preparing a taxoid of the formula I ##STR27##in which R represents a hydrogen atom or an acetyl, alkoxyacetyl oralkyl radical, R₁ represents a benzoyl radical or a radical R₂ --O--COin which R₂ represents an alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical, and Arrepresents an aryl radical, comprising the steps of esterifying aproduct of the formula VI: ##STR28## in which G₁ represents a hydrogenatom or an acetyl, alkoxyacetyl or alkyl radical or a hydroxy-protectinggroup, with a free acid of the formula VII: ##STR29## in which Ar and R₁are defined as above, R₃ represents a hydrogen atom or an alkoxy radicalcontaining 1 to 4 carbon atoms or a substituted or unsubstituted arylradical and R₄ represents a hydrogen atom, to give a compound of theformula II: ##STR30## treating the compound of formula II in acidicmedium to give a product of the formula I or a compound of the formulaIII: ##STR31## wherein G₁ of formula III represents a protecting groupthat is removed to give a product of formula I.
 2. The process of claim1, wherein the protecting group is replaced with hydrogen.
 3. Theprocess of claim 1, wherein the esterifying step further comprises usinga condensing agent chosen from carbodiimides and reactive carbonates andan activating agent chosen from aminopyridines in an organic solventchosen from ethers, ketones, esters, nitriles, aliphatic hydrocarbons,halogenated aliphatic hydrocarbons and aromatic hydrogens at atemperature ranging from -10° to 90° C.
 4. The process of claim 1,wherein the free acid of the esterifying step is in an anhydride form,and wherein the esterifying step is carried out in the presence of anactivating agent chosen from aminopyridines in an organic solvent chosenfrom ethers, esters, ketones, nitriles, aliphatic hydrocarbons,halogenated aliphatic hydrocarbons and aromatic hydrocarbons at atemperature ranging from 0° to 90° C.
 5. The process of claim 1, whereinthe free acid of the esterifying step is in a halide form or ananhydride form with an aliphatic or aromatic acid, and wherein theesterifying step is carried out in the presence of a base chosen fromtertiary aliphatic amines in an organic solvent chosen from ethers,esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatichydrocarbons, and aromatic hydrocarbons at a temperature ranging from 0°to 80° C.
 6. The process of claim 5, wherein the anhydride form of thefree acid is prepared in situ.
 7. The process of claim 1, wherein theacidic medium in the acid treatment step is an inorganic or organic acidin an organic solvent at a temperature ranging from -10° to 60° C. 8.The process of claim 7, wherein the acid is chosen from at least one ofhydrochloric, sulphuric, acetic, methanesulphonic,trifluoromethanesulphonic, and p-toluenesulphonic acids.
 9. The processof claim 7, wherein the solvent is chosen from alcohols, ethers, esters,halogenated aliphatic hydrocarbons, aromatic hydrocarbons, and nitriles.10. The process of claim 1, wherein the protecting group G₁ of formulaIII represents a 2,2,2-trichloroethoxycarbonyl or2-(2-trichloromethylpropoxy)carbonyl radical and is replaced by ahydrogen atom by treating with zinc or zinc combined with copper in thepresence of acetic acid at a temperature ranging from 30° to 60° C. orby treating with an inorganic or organic acid in solution with analiphatic alcohol containing 1 to 3 carbon atoms or an aliphatic esterin the presence of zinc or zinc combined with copper.
 11. The process ofclaim 10, wherein the organic acid is selected from hydrochloric andacetic acid.
 12. The process of claim 10, wherein the aliphatic ester isselected from ethyl acetate, isopropyl acetate, and n-butyl acetate. 13.The process of claim 1, wherein G₁ is an alkoxyacetyl radical and isreplaced by a hydrogen by treating in an alkaline medium using ammoniain an aqueous-alcoholic medium at a temperature of about 20° C. or bytreating with a zinc halide in methanol at a temperature of about 20° C.14. A process for preparing a taxoid of formula I ##STR32## in which Rrepresent a hydrogen atom or an acetyl, alkoxyacetyl or alkyl radical,R₁ represents a radical R₂ --O--CO-- in which R₂ represents an alkylradical, and Ar represents an aryl radical, comprising the steps ofesterifying a product of the formula VI: ##STR33## in which G₁represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl radicalor a hydroxy-protecting group, with a free acid of the formula VII:##STR34## in which Ar and R₁ are defined as above, R₃ represents ahydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or asubstituted or unsubstituted aryl radical, and R₄ represents a hydrogenatom, to give a compound of the formula II: ##STR35## treating thecompound of formula II in acidic medium to give a product of the formulaI or a compound of the formula III: ##STR36## wherein G₁ of formula IIIrepresents a protecting group that is removed to form a product offormula I.
 15. The process of claim 14, wherein the protecting group isreplaced by a hydrogen atom.
 16. The process of claim 14, wherein theesterifying step further comprises using a condensing agent chosen fromcarbodiimides and reactive carbonates and an activating agent chosenfrom aminopyridines in an organic solvent chosen from ethers, ketones,esters, nitriles, aliphatic hydrocarbons, halogenated aliphatichydrocarbons, and aromatic hydrocarbons at a temperature ranging from-10° to 90° C.
 17. The process of claim 14, wherein the free acid of theesterifying step is in an anhydride form, and wherein the esterifyingstep is carried out in the presence of an activating agent chosen fromaminopyridines in an organic solvent chosen from ethers, esters,ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatichydrocarbons, and aromatic hydrocarbons at a temperature ranging from 0°to 90° C.
 18. The process of claim 14, wherein the free acid of theesterifying step is in a halide form or an anhydride form with analiphatic or aromatic acid, and wherein the esterifying step is carriedout in the presence of a base chosen from tertiary aliphatic amines inan organic solvent chosen from ethers, esters, ketones, nitriles,aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, and aromatichydrocarbons at a temperature ranging from 0° to 80° C.
 19. The processof claim 18, wherein the anhydride form of the free acid is prepared insitu.
 20. The process of claim 14, wherein the acidic medium in the acidtreatment step is an inorganic or organic acid in an organic solvent ata temperature ranging from -10° to 60° C.
 21. The process of claim 20,wherein the acid is chosen from at least one of hydrochloric, sulphuric,acetic, methanesulphonic, trifluoromethanesulphonic, andp-toluenesulphonic acids.
 22. The process of claim 20, wherein thesolvent is chosen from alcohols, ethers, esters, halogenated aliphatichydrocarbons, aromatic hydrocarbons, and nitriles.
 23. The process ofclaim 14, wherein the protecting group G₁ of formula III represents a2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonylradical and is replaced by a hydrogen atom by treating with zinc or zinccombined with copper in the presence of acetic acid at a temperatureranging from 30° to 60° C. or by treating with an inorganic or organicacid in solution in an aliphatic alcohol containing 1 to 3 carbon atomsor an aliphatic ester in the presence of zinc or zinc combined withcopper.
 24. The process of claim 23, wherein the organic acid isselected from hydrochloric and acetic acid.
 25. The process of claim 23,wherein the aliphatic ester is selected from ethyl acetate, isopropylacetate, and n-butyl acetate.
 26. The process of claim 14, wherein G₁ isan alkoxyacetyl radical and is replaced by a hydrogen atom by treatingin an alkaline medium using ammonia in an aqueous-alcoholic medium at atemperature of about 20° C. or by treating with a zinc halide inmethanol at a temperature of about 20° C.
 27. A process for preparing ataxoid of the formula I: ##STR37## in which R represents a hydrogen atomor an acetyl, alkoxyacetyl or alkyl radical, R₁ represents a benzoylradical or a radical R₂ --O--CO-- in which R₂ represents an alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl orheterocyclyl radical, and Ar represents an aryl radical, comprising thesteps ofreacting a compound of the formula XXII: ##STR38## with analkali metal halide or an alkali metal azide or a quaternary ammoniumsalt or an alkali metal phosphate in an organic solvent to form acompound of the formula VI: ##STR39## in which G₁ represents a hydrogenatom or an acetyl, alkoxyacetyl or alkyl radical or a hydroxy protectinggroup, esterifying the compound of formula VI with a free acid of theformula VII: ##STR40## in which Ar and R₁ are defined as above, R₃represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbonatoms or a substituted or unsubstituted aryl radical and R₄ represents ahydrogen atom, to give a compound of the formula II: ##STR41## treatingthe compound of formula II in acidic medium to give a product of theformula I or a compound of the formula III: ##STR42## wherein G₁represents a protecting group that is removed to give a product offormula I.
 28. The process of claim 27, wherein the protecting group isreplaced with hydrogen.
 29. The process of claim 27, wherein theesterifying step further comprises using a condensing agent chosen fromcarbodiimides and reactive carbonates and an activating agent chosenfrom aminopyridines in an organic solvent chosen from ethers, ketones,esters, nitriles, aliphatic hydrocarbons, halogenated aliphatichydrocarbons, and aromatic hydrocarbons at a temperature ranging from-10° to 90° C.
 30. The process of claim 27, wherein the free acid of theesterifying step is in an anhydride form, and wherein the esterifyingstep is carried out in the presence of an activating agent chosen fromaminopyridines in an organic solvent chosen from ethers, esters,ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatichydrocarbons, and aromatic hydrocarbons at a temperature ranging from 0°to 90° C.
 31. The process of claim 27, wherein the free acid of theesterifying step is in a halide form or an anhydride form with analiphatic or aromatic acid, and wherein the esterifying step is carriedout in the presence of a base chosen from tertiary aliphatic amines inan organic solvent chosen from ethers, esters, ketones, nitriles,aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, and aromatichydrocarbons at a temperature ranging from 0° to 80° C.
 32. The processof claim 31, wherein the anhydride form of the free acid is prepared insitu.
 33. The process of claim 27, wherein the acid medium of the acidtreatment step is an inorganic or organic acid in an organic solvent ata temperature ranging from -10° to 60° C.
 34. The process of claim 33,wherein the acid is chosen from at least one of hydrochloric, sulphuric,acetic, methanesulphonic, trifluoromethanesulphonic, andp-toluenesulponic acids.
 35. The process of claim 33, wherein thesolvent is chosen from alcohols, ethers, esters, halogenated aliphatichydrocarbons, aromatic hydrocarbons, and nitriles.
 36. The process ofclaim 27, wherein the protecting group G₁ of formula III represents a2,2,2-trichloroethoxycarbonyl or 2-(2-trichloromethylpropoxy)carbonylradical and is replaced by a hydrogen atom by treating with zinc or zinccombined with copper in the presence of acetic acid at a temperatureranging from 30° to 60° C. or by treating with an inorganic or organicacid in solution in an aliphatic alcohol containing 1 to 3 carbon atomsor an aliphatic ester in the presence of zinc or zinc combined withcopper.
 37. The process of claim 36, wherein the organic acid isselected from hydrochloric and acetic acid.
 38. The process of claim 36,wherein the aliphatic ester is selected from ethyl acetate, isopropylacetate, and n-butyl acetate.
 39. The process of claim 27, wherein G₁ isan alkoxyacetyl radical and is replaced by a hydrogen by treating in analkaline medium using ammonia in an aqueous-alcoholic medium at atemperature of about 20° C. or by treating with a zinc halide inmethanol at a temperature of about 20° C.
 40. A process for preparing ataxoid of the formula I: ##STR43## in which R represents a hydrogen atomor an acetyl, alkoxyacetyl or alkyl radical, R₁ represents a benzoylradical or a radical R₂ --O--CO-- in which R₂ represents an alkyl,alkenyl, alkynyl, cycloalky, cycloalkenyl, bicycloalkyl, phenyl orheterocyclyl radical, and Ar represents an aryl radical, comprising thesteps ofreacting a compound of the formula XXII: ##STR44## with analkali metal halide or an alkali metal azide or a quaternary ammoniumsalt or an alkali metal phosphate in an organic solvent to form acompound of the formula VI: ##STR45## in which G₁ represents a hydrogenatom or an acetyl, alkoxyacetyl or alkyl radical or a hydroxyprotectinggroup, esterifying a compound of the formula VI with a free acid of theformula VII: ##STR46## in which Ar and R₁ are defined as above, R₃ andR₄, which are identical or different, represent an alkyl radicalcontaining 1 to 4 carbon atoms or an aralkyl radica whose alkyl portioncontains 1 to 4 carbon atoms or an aryl radical, or R₃ represents atrihalomethyl radical or a phenyl radical substituted by a trihalomethylradical and R₄ represents a hydrogen atom, or R₃ and R₄ form, togetherwith the carbon atom to which they are attached, a 4- to 7-memberedring, to give, after treating in acidic medium, a compound of theformula IV: ##STR47## and acylating the compound of formula IV withbenzoyl chloride or a reactive derivative of the formula:

    R.sub.2 --O--CO--X

in which X represents a halogen atom or a residue --O--R₂ or--O--CO--O--R₂ and R₂ is as defined above, to give a product of formulaI or a compound of formula III ##STR48## wherein G₁ represents aprotecting group that is removed to give a product of formula I.
 41. Theprocess of claim 40, wherein the protecting group is replaced by ahydrogen atom.
 42. The process of claim 40, wherein the esterifying stepfurther comprises using a condensing agent chosen from carbodiimides andreactive carbonates and an activating agent chosen from aminopyridinesin an organic solvent chosen from ethers, ketones, esters, nitriles,aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, and aromatichydrocarbons at a temperature ranging from -10° to 90° C.
 43. Theprocess of claim 39, wherein the free acid of the esterifying step is inan anhydride form, and wherein the esterifying step is carried out inthe presence of an activating agent chosen from aminopyridines in anorganic solvent chosen from ethers, esters, ketones, nitriles, aliphatichydrocarbons, halogenated aliphatic hydrocarbons, and aromatichydrocarbons at a temperature ranging from 0° to 90° C.
 44. The processof claim 40, wherein the free acid of the esterifying step is in ahalide form or an anhydride form with an aliphatic or aromatic acid, andwherein the esterifying step is carried out in the presence of a basechosen from tertiary aliphatic amines in an organic solvent chosen fromethers, esters, ketones, nitriles, aliphatic hydrocarbons, halogenatedaliphatic hydrocarbons, and aromatic hydrocarbons at a temperatureranging from 0° to 80° C.
 45. The process of claim 40, wherein the acidmedium of the acid treatment step is an inorganic or organic acid in anorganic solvent at a temperature ranging from 0° to 50° C.
 46. Theprocess of claim 45, wherein the acid is chosen from hydrochloric,sulphuric, and formic acids.
 47. The process of claim 45, wherein thesolvent is chosen from alcohols containing 1 to 3 carbon atoms.
 48. Theprocess of claim 40, wherein the acylating step further comprises usingan inert organic solvent in the presence of an inorganic or organicbase.
 49. The process of claim 48, wherein the inert organic solvent ischosen from esters, and halogenated aliphatic hydrocarbons.
 50. Theprocess of claim 40, wherein the protecting group G₁ of formula IIIrepresents a 2,2,2-trichloroethoxycarbonyl or2-(2-trichloromethyl-propoxy)carbonyl radical and is replaced by ahydrogen atom by treating with zinc or zinc combined with copper in thepresence of acetic acid at a temperature ranging from 30° to 60° C. orby treating with an inorganic or organic acid in solution in analiphatic alcohol containing 1 to 3 carbon atoms or an aliphatic esterin the presence of zinc or zinc combined with copper.
 51. The process ofclaim 43, wherein the anhydride form of the free acid is prepared insitu.
 52. The process of claim 50, wherein the aliphatic ester isselected from ethyl acetate, isopropyl acetate, and n-butyl acetate. 53.The process of claim 40, wherein G₁ is an alkoxyacetyl radical and isreplaced by a hydrogen by treating in an alkaline medium using ammoniain an aqueous-alcoholic medium at a temperature of about 20° C. or bytreating with a zinc halide in methanol at a temperature of about 20° C.54. A process for preparing a taxoid of the formula I: ##STR49## inwhich R represents a hydrogen atom or an acetyl, alkoxyacetyl or alkylradical, R₁ represents a benzoyl radical or a radical R₂ --O--CO-- inwhich R₂ represents an alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl radical, and Arrepresents an aryl radical comprising the steps ofreacting a compound ofthe formula XXII: ##STR50## in which G₁ represents a hydrogen atom or anacetyl or alkoxyacetyl radical or a hydroxy-protecting group, with analkali metal halide or an alkali metal azide or a quaternary ammoniumsalt or an alkali metal phosphate in an organic solvent to form acompound of the formula VI: ##STR51## esterifying the compound of theformula VI with an acid of the formula XXVI: ##STR52## in which Ar andR₁ are defined as above, G₃ represents a hydroxy-protecting group, or anactivated derivative of the acid of formula XXVI, to give a compound ofthe formula XXVII: ##STR53## replacing the protecting group G₃ withhydrogen to give a product of formula I and when G₁ represents aprotecting group, replacing said G₁ protecting group to give a productof formula I.
 55. The process of claim 54, wherein the G₁ protectinggroup is replaced by a hydrogen atom.
 56. The process of claim 54,wherein the esterifying step further comprises using a condensing agentchosen from carbodiimides and reactive carbonates and an activatingagent chosen from aminopyridines in an organic solvent chosen fromethers, ketones, esters, nitriles aliphatic hydrocarbons, halogenatedaliphatic hydrocarbons, and aromatic hydrocarbons at a temperatureranging from -10° to 90° C.
 57. The process of claim 54, wherein theacid of the esterifying step is in an anhydride form, and wherein theesterifying step is carried out in the presence of an activating agentchosen from aminopyridines in an organic solvent chosen from ethers,esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatichydrocarbons, and aromatic hydrocarbons at a temperature ranging from 0°to 90° C.
 58. The process of claim 54, wherein the acid of theesterifying step is in a halide form or an anhydride form with analiphatic or aromatic acid, and wherein the esterifying step is carriedout in the presence of a base chosen from tertiary aliphatic amines inan organic solvent chosen from ethers, esters, ketones, nitriles,aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, and aromatichydrocarbons at a temperature ranging from 0° to 80° C.
 59. The processof claim 58, wherein the anhydride form of the acid is prepared in situ.60. The process of claim 54, wherein the protecting groups G₁ and G₃represent a 2,2,2-trichloroethoxycarbonyl or2-(2-trichloro-methylpropoxy)carbonyl radical and are replaced withhydrogen atoms by treating with zinc or zinc combined with copper in thepresence of acetic acid at a temperature of between 30° and 60° C. or bytreating with an inorganic or organic acid in solution in an aliphaticalcohol containing 1 to 3 carbon atoms or an aliphatic ester in thepresence of zinc or zinc combined with copper.
 61. The process of claim54, wherein the protecting group G₃ represents a silylated radical oracetal residue and is replaced with hydrogen by treating in acidicmedium in solution in an aliphatic alcohol containing 1 to 3 carbonatoms or aqueous hydrofluoric acid at a temperature ranging from 0° to40° C., followed by the replacement of the protecting group G₁ withhydrogen by treating with zinc or zinc combined with copper in thepresence of acetic acid at a temperature ranging from 30° to 60° C. orby treating with an inorganic or organic acid in solution in analiphatic alcohol containing 1 to 3 carbon atoms or an aliphatic esterin the presence of zinc or zinc combined with copper.
 62. The process ofclaim 53, wherein G₁ is an alkoxyacetyl radical and is replaced by ahydrogen by treating in an alkaline medium using ammonia in anaqueous-alcoholic medium at a temperature of about 20° C. or by treatingwith a zinc halide in methanol at a temperature of about 20° C.
 63. Theprocess of claim 60, wherein the organic acid is hydrochloric or aceticacid.
 64. The process of claim 60, wherein the aliphatic esterrepresents ethyl acetate, isopropyl acetate, or n-butyl acetate.
 65. Theprocess of claim 54, wherein G₃ represents a radical --CH₂ --Ph and isreplaced by a hydrogen atom using hydrogenolysis after replacing theprotecting group G₁.